Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103<sup>+</sup>CD11b<sup>+</sup><scp>DC</scp>s in the intestinal lamina propria

Scott, Charlotte; Zangerle-Murray, Tamsin; Beckham, Katherine S. H.; Douce, Gill; Mowat, Allan McI

doi:10.1002/eji.201444859

Cited by 25 publications

(19 citation statements)

References 49 publications

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“…CD4 and CD8 α were also differently expressed among the subsets whereas co‐stimulatory molecules, CD80 and CD86, were equally expressed. Recent studies have revealed that DCs can be classified into subsets based on XCR1 and CD172a expression . Consistent with the previous studies, CD11b − CD103 + DCs including PD‐L1 High and PD‐L1 Low subsets expressed XCR1 but not CD172a whereas CD11b + CD103 + and CD11b + CD103 − DCs expressed CD172a but not XCR1.…”

Section: Resultssupporting

confidence: 86%

Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells

et al. 2017

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Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3 regulatory T cells to regulate immune responses to beneficial or non-harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103 DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD-L1) -deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c cells. Four distinct subsets expressing CD103 and/or PD-L1 were identified, namely CD11b CD103 PD-L1 , CD11b CD103 PD-L1 , CD11b CD103 PD-L1 and CD11b CD103 PD-L1 . Among them, the CD11b CD103 PD-L1 DC subset highly induced Foxp3 T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor-β (TGF-β) activation, respectively. Exogenous TGF-β supplementation equalized the level of Foxp3 T-cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF-β is determinant for the high Foxp3 T-cell induction by CD11b CD103 PD-L1 DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b CD103 PD-L1 DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF-β activation.

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Section: Resultssupporting

confidence: 86%

Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells

et al. 2017

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“…The same group subsequently showed that treatment with CD47-Fc conferred protection via a Th17-dependent mechanism [ 67 ]. Consistent with these data, a recent study by a different group found decreased numbers of Th17 cells in healthy intestinal mucosa of cd47 -null and SIRPα signaling-deficient mice, and a corresponding defective Th17 response to Citrobacter infection [ 68 ]. In this context, our data indicates that a defective Th17 response may contribute to the decreased resistance of cd47 -null mice to C .…”

Section: Discussionsupporting

confidence: 71%

CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis

et al. 2015

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CD47 is a widely expressed receptor that regulates immunity by engaging its counter-receptor SIRPα on phagocytes and its secreted ligand thrombospondin-1. Mice lacking CD47 can exhibit enhanced or impaired host responses to bacterial pathogens, but its role in fungal immunity has not been examined. cd47 -/- mice on a C57BL/6 background showed significantly increased morbidity and mortality following Candida albicans infection when compared with wild-type mice. Despite normal fungal colonization at earlier times, cd47 -/- mice at four days post-infection had increased colonization of brain and kidneys accompanied by stronger inflammatory reactions. Neutrophil and macrophage numbers were significantly elevated in kidneys and neutrophils in the brains of infected cd47 -/- mice. However, no defect in phagocytic activity towards C. albicans was observed in cd47 -/- bone-marrow-derived macrophages, and neutrophil and macrophage killing of C. albicans was not impaired. CD47-deficiency did not alter the early humoral immune response to C. albicans. Th1, Th2, and Th17 population of CD4+ T cells were expanded in the spleen, and gene expression profiles of spleen and kidney showed stronger pro-inflammatory signaling in infected cd47 -/- mice. The chemoattractant chemokines MIP-2α and MIP-2β were highly expressed in infected spleens of cd47 -/- mice. G-CSF, GM-CSF, and the inflammasome component NLRP3 were more highly expressed in infected cd47 -/- kidneys than in infected wild-type controls. Circulating pro- (TNF-α, IL-6) and anti-inflammatory cytokines (IL-10) were significantly elevated, but IL-17 was decreased. These data indicate that CD47 plays protective roles against disseminated candidiasis and alters pro-inflammatory and immunosuppressive pathways known to regulate innate and T cell immunity.

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“… 9 , 10 CX3CR1 was virtually absent in all colonic DC (see Figure 2 E ) but was expressed by macrophages, 17 whereas the GI-tract homing β7 integrin was expressed by the majority of colonic DC, with all CD103 + DC being positive. SIRPα, which regulates homeostatic properties of intestinal DC, 44 was typically coexpressed with the inhibitory receptor Ig-like transcript 3 (ILT3), 45 with no differences between CD103 - SIRPα + and CD103 + SIRPα + DC; CD103 + SIRPα − DC were ILT3 − . Conversely, ILT3 − DC displayed a higher expression of the costimulatory molecule CD40 (see Figure 2 E ).…”

Section: Resultsmentioning

confidence: 99%

Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon

Bernardo

Durant

Mann

et al. 2016

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsMost knowledge about gastrointestinal (GI)-tract dendritic cells (DC) relies on murine studies where CD103+ DC specialize in generating immune tolerance with the functionality of CD11b+/− subsets being unclear. Information about human GI-DC is scarce, especially regarding regional specifications. Here, we characterized human DC properties throughout the human colon.MethodsPaired proximal (right/ascending) and distal (left/descending) human colonic biopsies from 95 healthy subjects were taken; DC were assessed by flow cytometry and microbiota composition assessed by 16S rRNA gene sequencing.ResultsColonic DC identified were myeloid (mDC, CD11c+CD123−) and further divided based on CD103 and SIRPα (human analog of murine CD11b) expression. CD103-SIRPα+ DC were the major population and with CD103+SIRPα+ DC were CD1c+ILT3+CCR2+ (although CCR2 was not expressed on all CD103+SIRPα+ DC). CD103+SIRPα- DC constituted a minor subset that were CD141+ILT3−CCR2−. Proximal colon samples had higher total DC counts and fewer CD103+SIRPα+ cells. Proximal colon DC were more mature than distal DC with higher stimulatory capacity for CD4+CD45RA+ T-cells. However, DC and DC-invoked T-cell expression of mucosal homing markers (β7, CCR9) was lower for proximal DC. CCR2 was expressed on circulating CD1c+, but not CD141+ mDC, and mediated DC recruitment by colonic culture supernatants in transwell assays. Proximal colon DC produced higher levels of cytokines. Mucosal microbiota profiling showed a lower microbiota load in the proximal colon, but with no differences in microbiota composition between compartments.ConclusionsProximal colonic DC subsets differ from those in distal colon and are more mature. Targeted immunotherapy using DC in T-cell mediated GI tract inflammation may therefore need to reflect this immune compartmentalization.

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Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103⁺CD11b⁺DCs in the intestinal lamina propria

Cited by 25 publications

References 49 publications

Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells

Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells

CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis

Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon

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Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103+CD11b+DCs in the intestinal lamina propria

Cited by 25 publications

References 49 publications

Mesenteric lymph node CD11b− CD103+ PD‐L1High dendritic cells highly induce regulatory T cells

Mesenteric lymph node CD11b− CD103+ PD‐L1High dendritic cells highly induce regulatory T cells

CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis

Chemokine (C-C Motif) Receptor 2 Mediates Dendritic Cell Recruitment to the Human Colon but Is Not Responsible for Differences Observed in Dendritic Cell Subsets, Phenotype, and Function Between the Proximal and Distal Colon

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Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103⁺CD11b⁺DCs in the intestinal lamina propria

Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells

Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells